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ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT Update revision : 22 February 2005 9th ACCSQ-PPWG Meeting, Philippines, 21-24 Feb 2005 LIST OF CONTENTS Page INTRODUCTION OBJECTIVES SCOPES DESIGN 4.1 General 4.2 Photostability Testing 4.3 Selection of Batches 4.4 Specification (Testing Parameter) 4.5 Testing Frequency 4.6 Storage Condition (General Case) 4.6.1 For NCE Drug Products 4.6.2 For Generics and Variation (MaV and MiV if appropriate) Products 10 4.6.3 Drug Products Intended for Storage in a Refrigerator 10 4.6.4 Drug Products Intended for Storage in a Freezer 11 4.6.5 Drug Products Intended for Storage Below -20ºC 11 4.7 Container Closure System 11 4.8 Evaluation 12 4.9 Stability Commitment 14 4.10 Statements/Labeling ANNEXES 15 16 5.1 Protocol of Stability Study (example) 16 5.2 Report Format (example) 20 5.3 Reduced Design (Bracketing and Matrixing) 27 5.4 Extrapolation of Data 29 5.5 Examples of Types, Thickness and Permeability Coefficient of Packaging Materials 30 GLOSSARY 32 REFERENCES 36 INTRODUCTION 1.1 The objective of a stability study is to determine the shelf-life, namely the time period of storage at a specified condition within which the drug product still meets its established specifications 1.2 Stability is an essential factor of quality, safety and efficacy of a drug product A drug product, which is not of a sufficient stability, can result in changes in physical (like hardness, dissolution rate, phase separation, etc.) as well as in chemical characteristics (formation of high risk decomposition substances) Microbiological instability of a sterile drug product could also be hazardous 1.3 The stability study consists of a series of tests in order to obtain an assurance of stability of a drug product, namely maintenance of the specifications of the drug product packed in its specified packaging material and stored in the established storage condition within the determined time period OBJECTIVES This guideline is intended to provide recommendations on the core stability study package required for drug products, but leaves sufficient flexibility to encompass the variety of different practical situations that may be encountered due to specific scientific considerations and characteristics of the products being evaluated This guideline can also be used to propose shelf-life based on the stability data generated from the study package SCOPES This guideline addresses the information to be submitted in application for marketing authorization of drug products in ASEAN countries including examples of a protocol of stability study, a report format, reduced design and extrapolation of data, and examples of types, thickness and permeability coefficient which are covered in Annexes The drug products covered in this guideline include NCE, Generics and Variations (MaV and MiV) but exclude drug products containing vitamin and mineral preparations DESIGN 4.1 General The design of the stability studies for the product should be based on knowledge of the behavior and properties of the drug substance and dosage form 4.2 Photostability Testing Photostability testing should be conducted on at least one primary batch of the drug product if appropriate The standard conditions for photostability testing are described in ICH Q1B 4.3 Selection of Batches At the time of submission, stability data should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing - For NCE stability data should be provided on at least three primary batches of the drug products - For Generics and Variations the following will apply : • For conventional dosage forms (e.g., immediate release solid dosage forms, solutions) and when the drug substances are known to be stable, stability data on at least two pilot scale batches are acceptable • For critical dosage forms (e.g., prolonged release forms) or when the drug substances are known to be unstable, stability data on three primary batches are to be provided Two of the three batches should be at least of a pilot scale; the third batch may be smaller - The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing - Where possible, batches of the drug product should be manufactured by using different batches of the drug substance - Stability studies should be performed on each individual strength and container size of the drug product unless bracketing or matrixing is applied Other supporting data can be provided 4.4 Specification (Testing Parameter) Specification is a list of tests, reference to analytical procedures, and proposed acceptance criteria, including the concept of different acceptance criteria for release and shelf-life specifications Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes, preservative content (e.g antioxidant, antimicrobial preservative), and functionality tests (e.g., for a dose delivery system) The analytical procedure should be fully validated and stability indicating according to ASEAN guideline on Analytical Validation Whether and to what extent replication should be performed will depend on the results from validation studies The following list of parameters for each dosage form is presented as a guide for the types of tests to be included in a stability study In general, appearance, assay and degradation products should be evaluated for all dosage forms For generic products, degradation products should be limited to compendial requirements The list of tests presented for each dosage form is not intended to be exhaustive, nor is expected that every listed test be included in the design of a stability protocol for a particular drug product (for example, a test for odour should be performed only when necessary and with consideration for analyst safety) Furthermore, it is not expected that every listed test be performed at each time point The storage orientation of the product, i.e., upright versus inverted, may need to be included in a protocol where there has been a change in the container/closure system Tablets Tablets should be evaluated for appearance, odour, colour, assay, degradation products, dissolution, moisture and hardness/friability Capsules Hard gelatin capsules should be evaluated for appearance (including brittleness), colour, and odour of content, assay, degradation products, dissolution, moisture and microbial content Testing of soft gelatin capsules should include appearance, colour, and odour of content, assay, degradation products, dissolution, microbial content, pH, leakage, and pellicle formation In addition, the fill medium should be examined for precipitation and cloudiness Emulsions An evaluation should include appearance (including phase separation), colour, odour, assay, degradation products, pH, viscosity, microbial limits, preservative content, and mean size and distribution of dispersed globules Oral Solutions and Suspensions The evaluation should include appearance (including formation of precipitate, clarity for solutions), colour, odour, assay, degradation products, pH, viscosity, preservative content and microbial limits Additionally for suspensions, redispersibility, rheological properties and mean size and distribution of particles should be considered After storage, sample of suspensions should be prepared for assay according to the recommended labeling (e.g shake well before using) Oral Powders for Reconstitution Oral powders should be evaluated for appearance, colour, odour, assay, degradation products, moisture and reconstitution time Reconstituted products (solutions and suspensions) should be evaluated as described in Oral Solutions and Suspensions above, after preparation according to the recommended labeling, through the maximum intended use period Metered-dose Inhalations and Nasal Aerosols Metered-dose inhalations and nasal aerosols should be evaluated for appearance (including content, container, valve, and its components), colour, taste, assay, degradation products, assay for co-solvent (if applicable), dose content uniformity, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight) and extractables/leachables from plastic and elastomeric components Samples should be stored in upright and inverted/on-the-side orientations For suspension-type aerosols, the appearance of the valve components and container’s contents should be evaluated microscopically for large particles and changes in morphology of the drug surface particles, extent of agglomerates, crystal growth, as well as foreign particulate matter These particles lead to clogged valves or non-reproducible delivery of a dose Corrosion of the inside of the container or deterioration of the gaskets may adversely affect the performance of the drug product Nasal Sprays : Solutions and Suspensions The stability evaluation of nasal solutions and suspensions equipped with a metering pump should include appearance, colour, clarity for solution, assay, degradation products, preservative and antioxidant content, microbial limits, pH, particulate matter, unit spray medication content uniformity, number of actuations meeting unit spray content uniformity per container, droplet and/or particle size distribution, weight loss, pump delivery, microscopic evaluation (for suspensions), foreign particulate matter and extractable/bleachable from plastic and elastomeric components of the container, closure and pump Topical, Ophthalmic and Otic Preparations Included in this broad category are ointments, creams, lotions, paste, gel, solutions and non-metered aerosols for application to the skin Topical preparations should be evaluated for appearance, clarity, colour, homogenity, odour, pH, resuspendability (for lotions), consistency, viscosity, particle size distribution (for suspensions, when feasible), assay, degradation products, preservative and antioxidant content (if present), microbial limits/sterility and weight loss (when appropriate) Evaluation of ophthalmic or otic products (e.g., creams, ointments, solutions, and suspensions) should include the following additional attributes: sterility, particulate matter, and extractable Evaluation of non-metered topical aerosols should include: appearance, assay, degradation products, pressure, weight loss, net weight dispensed, delivery rate, microbial limits, spray pattern, water content, and particle size distribution (for suspensions) Suppositories Suppositories should be evaluated for appearance, colour, assay, degradation o products, particle size, softening range, dissolution (at 37 C) and microbial limits 10 Small Volume Parenterals (SVPs) SVPs include a wide range of injection products such as Drug Injection, Drug for Injection, Drug Injectable Suspension, Drug for Injectable Suspension, and Drug Injectable Emulsion Evaluation of Drug Injection products should include appearance, clarity, colour, assay, preservative content (if present), degradation products, particulate matter, pH, sterility and pyrogen/endotoxin Stability studies for Drug for Injection products should include monitoring for appearance, colour, reconstitution time and residual moisture content The stability of Drug for Injection products should also be evaluated after reconstitution according to the recommended labeling Specific parameters to be examined at appropriate intervals throughout the maximum intended use period of the reconstituted drug product, stored under condition(s) recommended in labeling, should include appearance, clarity, odour, colour, pH, assay (potency), preservative (if present), degradation products/ aggregates, sterility, pyrogen/endotoxin and particulate matter The stability studies for Drug Injectable Suspension and Drug for Injectable Suspension products should also include particle size distribution, redispersibility and rheological properties in addition to the parameters cited above for Drug Injection and Drug for Injection products The stability studies for Drug Injectable Emulsion products should include, in addition to the parameters cited above for Drug Injection, phase separation, viscosity, and mean size and distribution of dispersed phase globules 11 Large Volume Parenterals (LVPs) Evaluation of LVPs should include appearance, colour, assay, preservative content (if present), degradation products, particulate matter, pH, sterility, pyrogen/endotoxin, clarity and volume 12 Drug Admixture For any drug product or diluents that is intended for use as an additive to another drug product, the potential for incompatibility exists In such cases, the drug product labeled to be administered by addition to another drug product (e.g parenterals, inhalation solutions), should be evaluated for stability and compatibility in admixture with the other drug products or with diluents both in upright and in inverted/on-the side orientations, if warranted A stability protocol should provide for appropriate tests to be conducted at 0-, 6- to 8- and 24-hour time points, or as appropriate over the intended use period at the recommended storage/use temperature(s) Tests should include appearance, colour, clarity, assay, degradation products, pH, particulate matter, interaction with the container/closure/device and sterility Appropriate supporting data may be provided in lieu of an evaluation of photo degradation 13 Transdermal Patches Stability studies for devices applied directly to the skin for the purpose of continuously infusing a drug substance into the dermis through the epidermis should be examined for appearance, assay, degradation products, in-vitro release rates, leakage, microbial limits/sterility, peel and adhesive forces, and the drug release rate 14 Freeze-dried Products Appearance of both freeze-dried and its reconstituted product, assay, degradation products, pH, water content and rate of solution 4.5 Testing Frequency For long-term studies, frequency of testing should be sufficient to establish the stability profile of the drug product The frequency of testing at the long term storage condition should normally be every months over the first year, every months over the second year, and annually thereafter through the proposed shelflife At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g., 0, 3, and months), from a 6-month study is recommended Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach significant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design Reduced designs, i.e., matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied, if justified; see Annex 5.3 Storage Condition Real Time Accelerated Alternatives to accelerated study Products NCE , Generics, and Variations (MaV and MiV) NCE , Generics, and Variations (MaV and MiV) Generics and Variations (MaVand MiV) Testing Frequency 0, 3, 6, 9, 12, 18, 24 months and annually through the proposed shelf-life 0, and months 0, and months 4.6 Storage Condition General Case In general, a drug product should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use (e.g., after reconstitution or dilution as recommended in the labeling) • Stability testing of the finished product after constitution or dilution, if applicable, should be conducted to provide information for the labeling on the preparation, storage condition, and in-use period of the constituted or diluted product This testing should be performed on the constituted or diluted product through the proposed in-use period on primary batches as part of the stability studies at initial and final time points and, if full shelf-life long term data will not be available before submission, at the last time point for which data will be available In general, this testing need not be repeated on commitment batches • Stability study is conducted under storage condition: TYPE OF CONTAINER/STUDY STORAGE CONDITION o o o o o o o o Products in primary containers permeable to water vapour 30 C ± C/75% RH ± 5% RH Products in primary containers impermeable to water vapour 30 C ± C/RH not specified Accelerated studies 40 C ± C/75% RH ± 5% RH Stress studies*) 40 C ± C/75% RH ± 5% RH *) Stress studies are necessary for analytical method validation, pharmaceutical formulation, identifying and monitoring potential degradants during stability testing The real time testing will be continued for a sufficient time beyond 12 months to cover shelf-life at appropriate test periods Data from the accelerated storage condition can be used to evaluate the effect of short-term excursions outside the label storage conditions (such as might occur during shipping) o • If submitted data is based on conditions that are less stressful (e.g 30 C/65% RH) than those required, the data should be accompanied by appropriate complementary data which will permit to conduct a proper scientific evaluation Factors to be taken into consideration will include: - Whether any instability is seen; - Whether data have also been provided under accelerated conditions; - Whether more protective packaging is provided/ required During the transition period, National authorities may decide either not to allocate a shelf life and to require more data before the product is approved, or to allocate a shelf life based on technical judgement and to require a commitment that the applicant will generate data under the new guideline conditions (30oC/75% RH, or 40oC/75% RH, or both) within a specified period A suitable label recommendation such as “Store below 30oC and protect from moisture” may also be applied • Additional data accumulated during the assessment period of the registration application should be submitted to the regulatory authorities if requested • Other storage conditions are allowable if justified, e.g., under the following circumstances : RESPONSIBILITY Persons in Charge Site / Department Responsibility John Doe R&D Physical and chemical tests John Doe R&D Microbiological tests SUMMARY This report presents the stability data on Paracetamol tablet 500 mg stored up to 60 months in the primary packaging used for marketing Any storage-related changes occuring in the finished product were monitored by means of stability-specified control tests The test design was based on the stability profile of the drug substance paracetamol and on the specific requirements of the dosage form Shelf-life: The product has a shelf-life of five years Storage Directions: The finished product is not labelled with any storage directions OBJECTIVE The objective of the present study on Paracetamol tablet 500 mg is the assessment of the stability profile for storage under real time and accelerated conditions The samples were in inverted position to ensure contact with the container closure system TEST MATERIAL The batches under stability testing are listed in the following table with further details: Scale Batch Size (Pack) Drug Substance Batch No Jakarta Production 2800 004 July 09, 1997 Jakarta Production 2800 005 July 16, 1997 Jakarta Production 2800 006 Manufacturing Batch No Date Site 500 mg/tab 001 July 02, 1997 500 mg/tab 002 500 mg/tab 003 Dosage 21 COMPOSITION tablet of Paracetamol contains : Composition Weight [mg] Paracetamol 500.00 Lactose 1H2O 79.00 Maize Starch 65.50 Pregelatinized Maize Starch 5.00 Talc 3.00 Colloidal Anhydrous Silica (Aerosil 200) 2.00 Magnesium Stearate 0.50 Total 655.00 PACKAGING The stability tests on the batches listed above are performed in the following primary packaging: The product is packed in PVC blister consisting of: • Push trough foil : Alufoil of 20 micron thickness, heat-seal lacquered, PVC layered (8 g/m2), hard temper, bright side finish silver-tinted • Forming foil : PVC foil of 250 micron thickness 22 STORAGE CONDITIONS AND TESTING INTERVALS The various samples of the packaged drug product have been / will be tested according to the following schedule: Storage Condition 30°C + 2°C/75% RH 12 18 24 36 48 60 X - X X X X X X X X X X X X X - - - - - - - + 5% RH 40°C + 2°C/75% RH + 5% RH ANALYTICAL PROCEDURES The stability tests on Paracetamol were performed according to the control tests of USP In the course of the stability testing the main emphasis was put on the stabilityrelevant test items as listed below: Test Item Control Test No Specification Hardness USP > 70 N Friability USP < 2% Degradation Product • p-aminophenol Microbial Contamination Content (LC) USP USP < 0.005% Total count < 102 CFU USP E.coli : absent 95.0 – 105.0 % Note: As mentioned in 2.1.2, 3.1 and 3.2, Disintegration Time and Dissolution should be added REFERENCE STANDARD Standard Paracetamol USP, 99.5%, was used 23 10 RESULTS The test results of the study are presented in the tables attached 10.1 Physical Stability The physical stability of Paracetamol tablet 500 mg proved to be unchanged after storage up to 60 months at 30oC/75% RH and after months under accelerated conditions at 40oC/75% RH The result obtained for the test item’s "appearance" was not changed significantly 10.2 Chemical Stability 10.2.1 Stability under Real time Conditions Storage for up to 60 months at 30oC/75% RH had no significant effect on the chemical stability of the drug product With regard to test item "Organic Impurity" only slight changes were observed The p-aminophenol concentration was below 0.005% The content of paracetamol did not change significantly after storage under real time conditions compared to initial assay of the batches 10.2.2 Stability under Accelerated Conditions Storage under accelerated conditions for months did not effect the chemical stability The content of paracetamol was not significantly changed compared to the initial value of the batches 11 DISCUSSION / CONCLUSIONS Storage under real time testing conditions causes insignificant change of assay results of paracetamol Significant changes in physical and chemical stabilities were not observed Since the long-term data and accelerated data show little or no change over time and little variability, a statistical analysis is considered unneecessary Shelf-life: Based on the result data the shelf-life has been established for five years Storage Directions: The product can be labelled with ”Store below 30oC” 24 Summary of Stability Study Result Table Drug Product : Dosage : Packaging : Paracetamol 500 mg/tablet PVC Blister Batch No : Storage Time [Months] Appearance Conditions Specifications White, roundflat tablet Hardness [N] Friability [%] Content : Paracetamol 500 mg > 70 N